Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.

Article Details

Citation

Lin YC, Lin JH, Chou CW, Chang YF, Yeh SH, Chen CC

Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.

Cancer Res. 2008 Apr 1;68(7):2375-83. doi: 10.1158/0008-5472.CAN-07-5807.

PubMed ID
18381445 [ View in PubMed
]
Abstract

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a K(i) value of 31.6 micromol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
AtorvastatinHistone deacetylase 2ProteinHumans
Unknown
Inhibitor
Details
FluvastatinHistone deacetylase 2ProteinHumans
Unknown
Inhibitor
Details
LovastatinHistone deacetylase 2ProteinHumans
No
Inhibitor
Details
PravastatinHistone deacetylase 2ProteinHumans
Unknown
Inhibitor
Details
SimvastatinHistone deacetylase 2ProteinHumans
Unknown
Inhibitor
Details